The NF-kB family of transcription factors plays a crucial role in many cellular responses. They exist as homodimers or heterodimers of 5 distinct proteins: p50, p52, p65/RelA, RelB and cRel (Li and Verma, 2002. Nat Rev Immunol 2:725-734; Hayden and Ghosh, 2004. Genes Dev 18:2195-2224). NF-kB activation typically occurs by nuclear translocation following inducible phosphorylation of inhibitory IkB proteins by the IKKa/b (IkB kinase) complex (Hayden and Ghosh, 2004. Genes Dev 18:2195-2224; Hoffmann, and Baltimore, 2006. Immunol Rev 210:171-186; Karin and Ben-Neriah, 2000. Annu Rev Immunol 18:621-663; Vallabhapurapu and Karin, 2009. Annu Rev Immunol 27:693-733). Activation of the major conventional or canonical subunits p50, p65/RelA and cRel by inflammatory cytokines such as TNFa and IL-1a/b requires IKKb while non-conventional or non-canonical p52 and RelB subunits require IKKa (Bonizzi and Karin, 2004. Trends Immunol 25:280-288; Hacker and Karin, 2006. Sci STKE 2006:re13). A multitude of functions have been attributed to canonical NF-kB subunits, which include roles in inflammation and immunity, as well as in cell proliferation and survival. A tumor-promoting function for NF-kB in lymphomas has been known for some time (Staudt, 2010. Cold Spring Harb Perspect Biol 2:a000109; Packham, 2008. Br J Haematol 143:3-15). NF-kB was implicated in the Ras pathway (Mayo et al., 1997. Science 278:1812-1815) but the role of NF-kB in solid malignancies, although suspected, was not clear. Recent studies in mice and human cell lines have defined a key role for NF-kB in K-Ras-induced lung cancer ((Barbie et al., 2009. Nature 462:108-112; Meylan et al., 2009. Nature 462:104-107; Basseres et al., 2010. Cancer Res 70:3537-3546). This is likely through NF-kB activation via IKKb and/or TBK1 kinase by oncogenic K-Ras (Barbie et al., 2009. Nature 462:108-112; Meylan et al., 2009. Nature 462:104-107; Basseres et al., 2010. Cancer Res 70:3537-3546). It is not known whether NF-kB plays a general or genetic mutation-specific role in lung cancer development. An additional key role of IKKb/NF-kB in inflammation-promoting non-tumor myeloid cell types has also been shown to be critical in solid malignancies (Maeda et al., 2005. Cell 121:977-990; Karin and Greten, 2005. Nat Rev Immunol 5:749-759; Greten et al., 2004. Cell 118:285-296; Takahashi et al., 2010. Cancer Cell 17:89-97).
Inhibition of NF-kB activation represents a promising avenue for therapeutic targeting of lung cancer. However, relatively little is known about the role and activation state of NF-kB in human lung cancer. Most importantly, the inter-relation between NF-kB activation state and disease progression and survival is not known. It is also not known whether NF-kB is only activated in response to specific genetic mutations, e.g., K-Ras mutations. In this respect, one of the main stumbling blocks is the lack of an appropriate functional readout of NF-kB activation in human lung cancer cells. Previous NF-kB signatures have been defined, but not in lung cancer cells (Hinata et al., 2003. Oncogene 22:1955-1964; Boehm et al., 2007. Cell 129:1065-1079; Hernandez et al., 2010. Cancer Res 70:4005-4014).